Alzheimer's and prion diseases: distinct pathologies, common proteolytic denominators

Abstract

Alzheimer's and prion pathologies are often seen as distinct neurodegenerative diseases, particularly because the infectious character of some prion-associated pathology makes this stand apart from classical neurodegenerative, age-related syndromes. Are there specific common denominators that could link the two diseases? It appears that betaAPP (beta-amyloid precursor protein) and PrP(c) (cellular prion protein), the 'guilty' proteins involved in these pathologies, undergo protein-kinase-C-regulated proteolysis by identical proteases of the disintegrin family. This cleavage occurs in an analogous way, in the middle of the 'toxic' Abeta and PrP(c)106-126 domains of betaAPP and PrP(c), respectively. As these two sequences trigger similar caspase-dependent and -independent cascades, this proteolytic attack could be seen as an inactivating process aimed at clearing cells of these endogenous 'toxins' and, thus, preventing the associated proteinaceous accumulation usually detected in affected brains. It is our opinion that targeting these disintegrins with specific 'activators' could be a suitable strategy to slow down, or even arrest, betaAPP and PrP(c)-related aggregation and toxicity.